Effect of Argatroban Plus Intravenous Alteplase vs Intravenous Alteplase Alone on Neurologic Function in Patients With Acute Ischemic Stroke: The ARAIS Randomized Clinical Trial.

Importance: Previous studies suggested a benefit of argatroban plus alteplase (recombinant tissue-type plasminogen activator) in patients with acute ischemic stroke (AIS). However, robust evidence in trials with large sample sizes is lacking. Objective: To assess the efficacy of argatroban plus alteplase for AIS. Design, Setting, and Participants: This multicenter, open-label, blinded end point randomized clinical trial including 808 patients with AIS was conducted at 50 hospitals in China with enrollment from January 18, 2019, through October 30, 2021, and final follow-up on January 24, 2022. Interventions: Eligible patients were randomly assigned within 4.5 hours of symptom onset to the argatroban plus alteplase group (n = 402), which received intravenous argatroban (100 µg/kg bolus over 3-5 minutes followed by an infusion of 1.0 µg/kg per minute for 48 hours) within 1 hour after alteplase (0.9 mg/kg; maximum dose, 90 mg; 10% administered as 1-minute bolus, remaining infused over 1 hour), or alteplase alone group (n = 415), which received intravenous alteplase alone. Both groups received guideline-based treatments. Main Outcomes and Measures: The primary end point was excellent functional outcome, defined as a modified Rankin Scale score (range, 0 [no symptoms] to 6 [death]) of 0 to 1 at 90 days. All end points had blinded assessment and were analyzed on a full analysis set. Results: Among 817 eligible patients with AIS who were randomized (median [IQR] age, 65 [57-71] years; 238 [29.1%] women; median [IQR] National Institutes of Health Stroke Scale score, 9 [7-12]), 760 (93.0%) completed the trial. At 90 days, 210 of 329 participants (63.8%) in the argatroban plus alteplase group vs 238 of 367 (64.9%) in the alteplase alone group had an excellent functional outcome (risk difference, -1.0% [95% CI, -8.1% to 6.1%]; risk ratio, 0.98 [95% CI, 0.88-1.10]; P = .78). The percentages of participants with symptomatic intracranial hemorrhage, parenchymal hematoma type 2, and major systemic bleeding were 2.1% (8/383), 2.3% (9/383), and 0.3% (1/383), respectively, in the argatroban plus alteplase group and 1.8% (7/397), 2.5% (10/397), and 0.5% (2/397), respectively, in the alteplase alone group. Conclusions and Relevance: Among patients with acute ischemic stroke, treatment with argatroban plus intravenous alteplase compared with alteplase alone did not result in a significantly greater likelihood of excellent functional outcome at 90 days. Trial Registration: ClinicalTrials.gov Identifier: NCT03740958.

Recombinant human insulin-like growth factor-1 promotes osteoclast formation and accelerates orthodontic tooth movement in rats.

BACKGROUND: IGF-1 may be an important factor in bone remodeling, but its mechanism of action on osteoclasts during orthodontic tooth movement is complex and unclear. METHODOLOGY: The closed-coil spring was placed between the left maxillary first molar and upper incisors with a force of 50 g to establish an orthodontic movement model. Eighty SD rats were randomized to receive phosphate buffer saline or 400 ng rhIGF-1 in the lateral buccal mucosa of the left maxillary first molar every two days. Tissue sections were stained for tartrate-resistant acidic phosphatase (TRAP), the number of TRAP-positive cells was estimated and tooth movement measured. RESULTS: The rhIGF-1 group exhibited evidential bone resorption and lacuna appeared on the alveolar bone compared to the control group. Moreover, the number of osteoclasts in compression side of the periodontal ligament in the rhIGF-1 group peaked at day 4 (11.37±0.95 compared to 5.28±0.47 in the control group) after the orthodontic force was applied and was significantly higher than that of the control group (p<0.01). Furthermore, the distance of tooth movement in the rhIGF-1 group was significantly larger than that of the control group from day 4 to day 14 (p<0.01), suggesting that rhIGF-1 accelerated orthodontic tooth movement. CONCLUSION: Our study has showed that rhIGF-1 could stimulate the formation of osteoclasts in the periodontal ligament, and accelerate bone remodeling and orthodontic tooth movement.

Recombinant human insulin-like growth factor-1 promotes osteoclast formation and accelerates orthodontic tooth movement in rats

Abstract Background: IGF-1 may be an important factor in bone remodeling, but its mechanism of action on osteoclasts during orthodontic tooth movement is complex and unclear. Methodology: The closed-coil spring was placed between the left maxillary first molar and upper incisors with a force of 50 g to establish an orthodontic movement model. Eighty SD rats were randomized to receive phosphate buffer saline or 400 ng rhIGF-1 in the lateral buccal mucosa of the left maxillary first molar every two days. Tissue sections were stained for tartrate-resistant acidic phosphatase (TRAP), the number of TRAP-positive cells was estimated and tooth movement measured. Results: The rhIGF-1 group exhibited evidential bone resorption and lacuna appeared on the alveolar bone compared to the control group. Moreover, the number of osteoclasts in compression side of the periodontal ligament in the rhIGF-1 group peaked at day 4 (11.37±0.95 compared to 5.28±0.47 in the control group) after the orthodontic force was applied and was significantly higher than that of the control group (p<0.01). Furthermore, the distance of tooth movement in the rhIGF-1 group was significantly larger than that of the control group from day 4 to day 14 (p<0.01), suggesting that rhIGF-1 accelerated orthodontic tooth movement. Conclusion: Our study has showed that rhIGF-1 could stimulate the formation of osteoclasts in the periodontal ligament, and accelerate bone remodeling and orthodontic tooth movement.

Somatic mutation profiling of liver and biliary cancer by targeted next generation sequencing.

Liver and biliary cancers are highly lethal cancer types lacking effective treatments. The somatic mutations, particularly those with low mutant allele frequencies, in Chinese patients with liver and biliary cancer have not been profiled, and the frequency of patients benefiting from targeted therapy has not been studied. The present study evaluated the tumor tissues of 45 Chinese patients with hepatocellular carcinoma (HCC) and 12 Chinese patients with biliary tract cancer (BTC) by targeted next generation sequencing, with an average coverage of 639×, to identify alterations in 372 cancer-related genes. A total of 263 variants were identified in 139 genes, with 85.6% of these variants not previously reported in the Catalogue Of Somatic Mutations In Cancer database, and the mutation profile was different from the current datasets, including The Cancer Genome Atlas dataset and the National Cancer Center Japan (NCC_JP) dataset. Patients with hepatitis B virus (HBV) infection harbored more mutations than those without HBV infection, and the mutations in HBV carriers occurred preferentially in genes involved in vascular endothelial growth factor signaling pathways. Mutations in fibroblast growth factor and RAS signaling pathways were enriched in patients with cirrhosis, and alterations in interleukin and transforming growth factor signaling pathways were more frequently identified in individuals with abnormal bilirubin expression. Of all the patients, 7% exhibited variants in the target of sorafenib, and 42% harbored variants in the targets of drugs that have been approved to treat other types of cancer. These findings indicate diverse HCC/BTC variants patterns in different populations, and that the mutation load and patterns are correlated with clinical features. Further clinical studies are now warranted to evaluate the efficacies of other targeted drugs besides sorafenib in the treatment of patients with liver and biliary cancer.

[Effect of local injection of rhTGF-α1 on osteoclasts during orthodontic tooth movement in rats].

PURPOSE: To investigate the effect of exogenous TGF-ß1 on improving periodontal tissues remodeling during orthodontic tooth movement in rats. METHODS: Eighty male SD rats were randomly divided into 2 groups. Rats in the experimental group were injected respectively with rhTGF-ß1 in dosages of 0.1 mL (5 ng/mL) in the buccal submucosal area of the molar every other day, while rats in the control group received equivalent volumes of PBS. Each group (n=40) was subdivided equally into 5 subgroups. An orthodontic appliance, consisting of a 5 mm nickel titanium closed coil spring, was ligated between the maxillary left incisor and first molar of each rat to deliver an initial force of 0.49N. Eight rats in each subgroup were sacrificed at one of the five time points (1, 4, 7, 10 and 14 days) after appliance placement. The distance of the tooth movement was measured by using stereomicroscope. Tissue sections around the first maxillary left molar were stained with tartrate-resistant acid phosphatase (TRAP) histochemistry to analyze the changes of the amount and distribution of osteoclasts on the compression side of tooth. Statistical analysis was performed using SPSS 17.0 software package. RESULTS: Molars treated with rhTGF-ß1 moved mesially more rapidly than the control group. The distance of tooth movement of the experimental group showed a significant increase compared with the control group at day 7 (P<0.05) and significant increase compared with the control group at day 10 and 14 (P<0.01). The number of TRAP positive cells appearing in the periodontal ligament space on the pressure side of the alveolar bone were increased markedly in experimental group. There were statistically significant differences in the amount of osteoclasts between experimental and control groups (P<0.01). CONCLUSIONS: Local injection of rhTGF-ß1 in the periodontal tissues can accelerate orthodontic tooth movement via enhancing the numbers of osteoclasts. At the histologic level, increased numbers of mononuclear osteoclasts are recruited and activated, resulting in greater amounts of alveolar bone resorption on the pressure side of the periodontal ligament.

Ex-situ liver surgery without veno-venous bypass.

AIM: To evaluate the results of hepatic resection with ex-situ hypothermic perfusion and without veno-venous bypass. METHODS: In 3 patients with liver tumor, the degree of the inferior vena cava and/or main hepatic vein involvement was verified when the liver was dissociated in the operation. It was impossible to resect the tumors by the routine hepatectomy, so the patients underwent ex-situ liver surgery, vein cava replacement and hepatic autotransplantation without veno-venous bypass. All surgical procedures were carried out or supervised by a senior surgeon. A retrospective analysis was performed for the prospectively collected data from patients with liver tumor undergoing ex-situ liver surgery, vein cava replacement and hepatic autotransplantation without veno-venous bypass. We also compared our data with the 9 cases of Pichlmayr's group. RESULTS: Three patients with liver tumor were analysed. The first case was a 60-year-old female with a huge haemangioma located in S1, S4, S5, S6, S7 and S8 of liver; the second was a 64-year-old man with cholangiocarcinoma in S1, S2, S3 and S4 and the third one was a 55-year-old man with a huge cholangiocarcinoma in S1, S5, S7 and S8. The operation time for the three patients were 6.6, 6.4 and 7.3 h, respectively. The anhepatic phases were 3.8, 2.8 and 4.0 h. The volume of blood loss during operation were 1200, 3100, 2000 mL in the three patients, respectively. The survival periods without recurrence were 22 and 17 mo in the first two cases. As for the third case complicated with postoperative hepatic vein outflow obstruction, emergency hepatic vein outflow extending operation and assistant living donor liver transplantation were performed the next day, and finally died of liver and renal failure on the third day. Operation time (6.7 ± 0.47 h vs 13.7 ± 2.6 h) and anhepatic phase (3.5 ± 0.64 h vs 5.7 ± 1.7 h) were compared between Pichlmayr's group and our series (P = 0.78). CONCLUSION: Ex-situ liver resection and liver autotransplantation has shown a potential for treatment of complicated hepatic neoplasms that are unresectable by traditional procedures.